Immunology最新文献

LAG-3⁺ regulatory T cells suppress the effector but not the proliferative response of naïve cognate antigen-specific CD4⁺ T cells in vivo. The Th1, Th2, and Th17 machineries in the suppressed CD4⁺ T cells are impaired. Genomic study of the suppressed T cells revealed enhanced T cell receptor signalling with up-regulation of immune checkpoints, including PD-1 and PD-L1, and down-regulation of pro-inflammatory pathways. Although oxidative metabolism is reduced, the suppressed T cells retain proliferative capacity and acquire LAG-3 expression with proliferation. They acquire the capacity of LAG-3⁺ regulatory T cells. They inhibit the IFN-γ response of co-cultured naïve CD4⁺ T cells in vitro. Upon adoptive transfer, they rescue mice from lethal autoimmune pulmonitis in a dose-dependent manner. Our results implied a mechanism for the maintenance of long-lasting antigen-specific tolerance.

Metabolic reprogramming is a hallmark of cancer, enabling tumour cells to flexibly adapt to fluctuating microenvironmental conditions, sustain uncontrolled proliferation, and acquire resistance to conventional therapies. Tumour metabolism is not limited to the classical Warburg effect but encompasses a dynamic interplay between glycolysis, oxidative phosphorylation (OXPHOS), fatty acid metabolism, and amino acid utilisation, each fine-tuned according to tissue context, tumour type, and stage of progression. Central regulators such as hypoxia-inducible factor-1 (HIF-1), MYC, p53, peroxisome proliferator-activated receptors (PPARs), oestrogen receptor (ER), and sterol regulatory element-binding proteins (SREBPs) orchestrate these pathways, linking nutrient availability to oncogenic signalling and transcriptional control. This review synthesises current evidence on these interconnected metabolic circuits and critically evaluates existing controversies, such as the dual reliance on glycolysis and OXPHOS, metabolic plasticity under therapeutic pressure, and the role of stromal–tumor metabolic crosstalk. Beyond established pathways, emerging areas are transforming our understanding of tumour metabolism. Single-cell metabolic profiling and spatial metabolomics reveal profound intratumoral heterogeneity, while immunometabolism highlights the bidirectional influence of cancer cells and immune cells within the tumour microenvironment (TME). Epigenetic regulation, driven by metabolites that serve as cofactors for chromatin-modifying enzymes, further integrates metabolic states with transcriptional reprogramming and therapy response. Translationally, targeting metabolic dependencies remains challenging; promising therapeutic opportunities are being developed, including inhibitors of lactate transporters, fatty acid oxidation, and glutamine metabolism. This review integrates mechanistic insights with translational perspectives, providing conceptual models, summary tables, and schematic illustrations to clarify complex networks and highlight clinically relevant opportunities. By mapping the evolving landscape of cancer metabolism, we aim to illuminate both the challenges and the therapeutic potential of exploiting metabolic vulnerabilities in oncology.

The European domestic ferret ( Mustela putorius furo ) is considered the gold standard small animal model for studying human and avian influenza virus infections. However, experimental characterisation of the transcriptomic response to interferon (IFN) stimulation and/or influenza virus infection has been limited, particularly in defining the induction of interferon-stimulated genes (ISGs), with most being computationally predicted. In this study, we present a comprehensive transcriptome-wide assessment of the ferret transcriptome following IFN-α treatment of a ferret lung (FRL) cell line, as well as in nasal turbinates from influenza A virus (IAV)-infected ferrets using long-read RNA sequencing. We have identified a panel of ferret genes orthologous to human ISGs that are upregulated both in response to IFN-α stimulation in vitro and IAV infection in vivo. We have also identified novel IFN-stimulated genes and transcripts. Furthermore, we observed elongation of the poly(A) tails of genes in the ribosome and Coronavirus Disease-19 pathways in response to IFN-α treatment in vitro, suggesting a relationship between poly(A) elongation and the antiviral responses of the host. These results illuminate the dynamics of the transcriptional innate immune response of the domestic ferret and provide an important resource for better utilising ferrets as a small animal model to study influenza virus infections.

Polyreactivity refers to the ability of antibodies to bind multiple unrelated antigens, encompassing polyspecificity and promiscuity. Here, we discuss the diverse molecular mechanisms underlying polyreactivity, including conformational dynamics, sequence- and structural characteristics of antigen-binding sites. The importance of polyreactive antibodies in immune defence and immune homeostasis is highlighted as well as their potential pathological consequences. Polyreactivity is seen as a continuum rather than a discrete property so that ultimately all antibodies possess some degree of polyreactivity. The challenges in defining antibody specificity are examined, and a shift towards quantitative thinking in antibody research is suggested. This would foster the adoption of novel methodologies to study complex antibody–antigen interactions at a systems level. Finally, the deeper understanding of polyreactivity's potential implications for the current antibody paradigm is critically evaluated.

Ankylosing spondylitis (AS) is a chronic immune-mediated disease marked by sustained joint inflammation and aberrant bone remodelling. Although chronic antigen exposure usually enforces terminal exhaustion, emerging evidence indicates that a subset of CD8⁺ T cells in AS evades canonical exhaustion programmes while expressing programmed cell death protein 1 (PD-1). These exhaustion-resistant cells retain effector function and likely contribute to persistent tissue inflammation and structural damage. In this review, we dissect the cellular and molecular basis of exhaustion resistance in AS CD8⁺ T cells and focus on the convergence of intermittent T cell receptor (TCR) stimulation, metabolic adaptation that preserves mitochondrial fitness, and co-stimulatory inputs from interleukin-15 (IL-15) and CD28. We propose an integrated three-axis model governing CD8⁺ T cell fate and functional persistence in the AS context shaped by human leukocyte antigen-B27 (HLA-B27) and the gut–joint axis. Clarifying these mechanisms refines current views of T cell dysfunction in chronic inflammation and highlights therapeutic strategies aimed at reprogramming pathogenic immunity in AS.

Understanding the innate immune memory induced by adjuvants provides an opportunity to improve vaccine efficacy by inducing nonspecific secondary responses alongside the intended adaptive defence against the target antigen. To understand the consequences of adjuvant-induced immune training, we treated mice with commercially available Sigma Adjuvant System (SAS) and performed functional assays of bone marrow-derived innate immune cells, assessed its functional consequences in vivo, determined the resulting haematopoietic stem and progenitor cell (HSPC) phenotypes, and extensively analyzed the HSPC transcriptome. SAS induced temporal shifts in HSPC frequencies, alterations in the circulating blood profile, and lowered proinflammatory output by macrophages. SAS-induced training caused disparate outcomes in models of inflammation and acute infection. Further, SAS enhanced antibody responses after primary immunisation, that were profoundly altered upon a secondary dose. Integrated transcriptional analysis revealed shifts in HSPCs defined by altered transcription factor activity and lineage-specific shifts in metabolic, epigenetic, myeloid, and kinase genes, resulting in enhanced antimicrobial neutrophil responsiveness and revealing regulators of central training. Together, these results contribute to the understanding of the plasticity and limitations of innate immune training.